PROJECT SUMMARY/ABSTRACT According to a recent JAMA report (August 8th, 2017), since 2005, after decades of decline, colorectal cancer (CRC) mortality rates have increased among individuals aged 40-54 years. These trends are consistent with recent increases in CRC incidence rates in younger people and at least 2 in 10 CRC diagnoses now occur in people aged less than 55 years. The recent increase in early-onset CRC (EOCRC) incidence strongly suggests that early life factors are operative. At least in part due to recent controversies concerning the role of dairy on overall health and replacement with other, mostly sugary drinks, milk intake in adolescents has also decreased in the past years. According to national data between 2003 and 2006 only 42% of adolescent boys and 13% of girls in the US met their Recommended Dietary Allowance (RDA) for calcium, a risk factor for late-onset CRC. Findings that human colon cancer cells exposed to high calcium exhibited decreased transcription of ?-catenin are of interest as the Wnt/?-catenin signaling pathway, which influences colon carcinogenesis, can be activated by high insulin or insulin-like growth factor 1 (IGF1). Our hypothesis is informed by physiology, i.e., that the up to 4-fold increase in IGF1 levels and the physiologic (non-obesity related) insulin resistance at puberty and the higher requirement for calcium renders adolescents particularly susceptible to low calcium intake. In particular, we hypothesize that low calcium intake may be especially harmful among obese or physically inactive adolescents, who in addition to physiological increases, are exposed to even higher insulin and IGF1 levels than normal weight or physically active adolescents. The influence of early life diet on adult cancer risk is extremely difficult to study. Therefore, we propose to address this critical gap in research by utilizing existing data from the Nurses' Health Study 2, a large ongoing prospective cohort of 45,774 younger nurses with validated high school diet and enriched with early-onset cases. In Aim 1, we will examine whether inverse associations between calcium intake during adolescence and EOCRC and early-onset advanced adenoma are stronger in women who were obese, physically inactive and consumed a western diet as adolescents. A crucial component of this proposal is the molecular sub-typing of early-onset colorectal neoplasia, which will provide insights into the mechanisms and refine risk estimates for subtypes. In Aim 2, we will assess whether inverse associations are stronger for tumors with CASR overexpression than for tumors with no CASR overexpression. If confirmed, this study may, for the first time, provide support for a potential link between calcium and obesity during adolescence and early-onset neoplasia; a promising hypothesis, with profound public health implications for adolescents in terms of cancer prevention. This proposal will also provide the groundwork for future molecular studies to elucidate pathways underlying EOCRC.